Development of mouse models of neurodegenerative diseases is critical for testing hypotheses about pathogenesis and for experimental therapeutics. A mouse model of Huntington's Disease (HD) has previously been created using genomic DNA. However models using cDNA constructs have the advantage of being much simpler to modify, since cDNA constructs can be altered easily. We have generated transgenic mice expressing an N-terminal fragment of huntington with an expanded repeat. These mice show a phenotype including progressive weight loss, ataxia, and uncoordination, leading to early death. Post mortem examination reveals intranuclear inclusions, the pathologic hallmark of HD. We will characterize the mice with the truncated construct in specific aim 1. We will further define the neuropathologic and neurochemical changes underlying the phenotype. In specific aim number 2 we will generate mice with a full length cDNA construct and determine similarities and differences in the pathology. In specific aim 3 we will use a construct with a myc-his tag in order to define the site of cleavage of huntingtin, and to purify associated proteins. Finally we will engineer inducible constructs which can target the transgene selectively to the regions of the cerebral cortex and striatum believed to be essential for the development of HD pathology. These experiments will clarify the pathogenesis of HD and provide models for future studies of experimental therapeutics.